About the FIRSTx Clinical Trial

FIRSTx is a Phase 2 study testing the safety and effectiveness of an investigational drug called CXA-10 designed to treat FSGS without steroids. This study will see if CXA-10 can reduce proteinuria while maintaining stable kidney function in people with FSGS. Throughout the course of the study, researchers will measure how different doses of CXA-10 impact proteinuria and carefully evaluate the kidney related and other effects of CXA-10. The study is taking place at approximately 20 centers across the United States.

About CXA-10

Animal studies suggest that CXA-10 appears to work by reducing inflammation in the glomeruli and helping to prevent scarring. CXA-10 has been evaluated in healthy volunteers. CXA-10 will be provided to study participants in the form of a pill taken once a day in the morning with food.

NephCure Funded Research: Dr. Michelle Denburg

In 2012, NephCure and the ASN Foundation awarded Dr. Michelle Denburg, a pediatric nephrologist at the Children’s Hospital of Philadelphia, a research grant to study vitamin D deficiency in the Nephrotic patient. Dr. Denburg is also a Co-Principal Investigator of the NephCure Kidney Network, a patient-reported outcomes registry for individuals with primary Nephrotic Syndrome diseases.

We were thrilled to speak with her recently to learn more about her work and the impact that the NephCure-ASN grant has had on her research.

Dr. Michelle Denburg

NKI: In 2012 you received the NephCure-ASN award for your research on vitamin D deficiency in the nephrotic patient. Can you tell us a little bit about your work that NephCure has helped fund?

Dr. Michelle Denburg: There are two studies that were related. One was an ancillary study to NEPTUNE, where we analyzed NEPTUNE baseline samples, measuring vitamin D metabolites and their hormonal regulators. We were looking at the relationships between what we already know in terms of Chronic Kidney Disease (CKD) and vitamin D, but specifically in terms of proteinuric glomerular diseases: the impact of proteinuria and relating some of the abnormalities of vitamin D metabolism to biopsy data and gene expression from the biopsies.

The other study is a trial of vitamin D supplementation in patients with Focal Segmental Glomerulosclerosis (FSGS) and other glomerular diseases with persistent proteinuria—basically, treatment resistant patients.

[editor’s note: The Nephrotic Syndrome Study Network, or NEPTUNE, is a long-term observational study that was formed to help understand the biology behind Nephrotic Syndrome. NEPTUNE has gathered health data and biological samples from close to 2,000 glomerular disease patients nationwide. Researchers can apply for grants, called “ancillary studies,” to conduct research on this de-identified patient data. Besides having helped fund the creation of NEPTUNE, NephCure also now helps provide the funding that make a number of the ancillary studies possible.]

NKI: I know this work has not yet been published, but is there anything from those studies that you can share with us at this time?

Dr. Denburg: There are some important things that we are going to be able to demonstrate and report. It’s fairly novel that we have measured vitamin D levels in the blood as well as the expression of vitamin D related genes in the kidney of people with glomerular disease. A lot of what we know about vitamin D metabolism comes from animal models. The fact that we have the NEPTUNE patients’ biopsy data and can relate the gene expression of these enzymes that are involved in vitamin D metabolism to their serum levels—this is highly novel from the research side.

From the patient and clinician side, this is the largest study of vitamin D related mineral metabolism in a glomerular cohort. The prior literature is small case studies—this study included several hundred people.

NKI: Do you think this work will change how patients are treated in their doctors’ offices?

Dr. Denburg: I can’t comment too much on the results of these studies which have not been published yet, but the findings could have important clinical implications. I think the nephrology community may need to consider updating our guidelines on vitamin D replacement in nephrotic patients. Our current guidelines are based on CKD in general. In other words, there is no guideline for patients with glomerular diseases who may have normal kidney function but a lot of proteinuria, or patients who have glomerular disease and CKD. And we know that patients with glomerular disease in particular have several obstacles to bone health.

One of my motivations behind this project is my interest in what we can modify to improve bone health in children and adolescents. Many of our patients are being exposed to a lot of steroids over time, and this is over the same period of time that they’re accruing the vast majority of their skeletal mass: about 90% of the skeleton is laid down before age 18. I’m interested in learning what we can do to modify and improve bone health in the face of therapies and illnesses we can’t avoid—that is, until we find a cure.

NKI: How do we separate the way steroid use affects bone health for glomerular disease patients to how having CKD in general affects bone health?

Dr. Denburg: I don’t know that glomerular patients need to be considered separately so much as have their unique risk within the CKD population considered. By definition, even someone with normal renal function who has glomerular disease is at CKD stage 1.

At a certain point, everybody starts losing bone. What kids come away with in terms of their skeleton by the time they enter the adult world is a huge determinant of their later fracture risk and other skeletal burden over time. You can never get that opportunity to address bone health back. You do accrue some cortical mass until age 30, but the majority of what you have is what you can accrue in your skeleton by age 18. Children and teenagers with glomerular disease have unique risk factors: high dose and long term steroid therapy, abnormalities in vitamin D metabolism, ongoing, persistent, heavy protein losses, and inflammation. There are a variety of risk factors that we can hopefully address.

NKI: The computable phenotype is another project I know you’re working on, and it sounds like it could be a game-changer. What is your role in that project and what about it excites you for the future of glomerular disease?

Dr. Denburg: That’s a very exciting avenue of research. Much of my effort on that is supported by the NephCure Kidney Network.

The computable phenotype is a way of identifying patients with glomerular disease through electronic health records (EHRs). It’s being developed in collaboration with PEDSnet [a large clinical data research network, composed of eight health institutions], so it represents over 5 million children and adolescents. The idea is that by running a computer programming code with essentially the push of a button, you can very rapidly say, here are the approximately 3,000 kids who have glomerular diseases across PEDSnet. And this is not static data, this is real life clinical care data. You could run the programmatic code again three months later and identify new cases. This is opposed to the traditional method where someone is sitting and going through the charts at each institution, which is not very time or cost effective.

The idea is that this is a means of rapid cohort identification. You can do observational studies on this population’s de-identified data. Or, with regulatory approval, you can contact patients and invite them to be in observational studies and clinical trials. You can also do trials in a more pragmatic way: you can invite patients to participate in a study where they don’t necessarily have to be followed by a typical regimented protocol with extra clinical visits, which is very laborious and cost-intensive. Instead, using this method, if we wanted to do a larger vitamin D study, we could consent individuals for a study and say, we’re going to randomize you to a group that either gets a lot of vitamin D or a group that gets a little vitamin D, abut then after that all your care is going to be your routine care with your clinician. Instead of having you come to separate appointments to track the effects of the vitamin D levels, we’re going to capture your data in regards to this study through your EHR. And we’ll leave it up to your own nephrologist to follow your levels and change your dosage. That’s what I mean by a pragmatic trial. I should say, the study has to lend itself to that—a high risk, new drug study is never going to be implemented in this manner.

NKI: And that more closely mimics real life; how a treatment would be used in real life vs. in a highly-regimented protocol.

Dr. Denburg: Right—so you lose a little of the very protocolized follow up, but you gain the real-life applicability and generalizability.

NKI: What impact did receiving the NephCure-ASN award have on your research?

Dr. Denburg: It was really mission-critical. I was a junior person, two years out of fellowship at that point, and it enabled me to build a research program. It helped me in getting my Career Development (K) Award from the National Institutes of Health, and the combination of those two awards allowed me to develop my research program and to have the ability to pursue multiple directions.

I like that I get to do patient-oriented research where I’m directly enrolling patients in studies of vitamin D treatment or assessing bone quality through imaging, but then I can also do studies where I’m accessing robust samples from NEPTUNE and entering this large data world. There are things you can do in each that really complement the other. And it’s the way to push things forward, moving between the analysis of large sources of data and then taking it back to the patient and vice versa. So I’m very grateful for the funding. I feel lucky. As pediatric nephrologists, Nephrotic Syndrome makes up a significant portion of patients we see and treat. Being a clinician who sees these patients really helps in keeping you attuned with what needs to be addressed from the research side—the patient care really drives the research questions.

We were delighted to learn more about Dr. Denburg’s research. Check back at www.NephCure.org to stay updated on her soon-to-be published work and other advances in the field. Thank you for your passion and commitment to improving the health of patients with Nephrotic Syndrome, Dr. Denburg!

Dr. Michelle Denburg, MD, MSCE, is an Assistant Professor of Pediatrics at the Perelman School of Medicine of the University of Pennsylvania and the Children’s Hospital of Philadelphia. Dr. Denburg’s research focuses on bone and mineral metabolism in childhood kidney diseases, including chronic kidney disease (CKD), glomerular disease, and urinary stone disease. In particular, she has pursued translational work in vitamin D-mediated innate immunity in nephrotic patients and ancillary studies of vitamin D metabolism and vitamin D-binding protein in pediatric patients with CKD. Her collaborative studies have focused on vitamin D metabolism and bone structure in children with CKD, nephrotic syndrome, and inflammatory bowel disease.

Dr. Denburg’s study of incident fracture risk in the Chronic Kidney Disease in Children (CKiD) cohort was the first to evaluate the burden of fractures in a large pediatric CKD cohort. She is a co-principal investigator in a project of the CKD Biomarkers Consortium that seeks to identify novel biomarkers for CKD progression in children. She has conducted several population-based studies of fracture risk in chronic diseases and CKD epidemiology using The Health Improvement Network (THIN) Database. She also has led the development of and serves as co-principal investigator of a Pediatric Glomerular Disease Learning Health System (LHS) within the PEDSnet clinical data research network. Dr. Denburg attended medical school at the Weill Medical College of Cornell University and received her Master of Science in Clinical Epidemiology from the University of Pennsylvania.

NephCure Funded Research: Dr. Hani Suleiman

Dr. Suleiman is using a Nobel-prize winning microscopy technique to look at the kidney cells injured in FSGS.

In 2014, the Nobel Prize for Chemistry went to a group of scientists who’ve created a new technique to change the scale at which we are able to see cell structures. In the same year, NephCure awarded a Young Investigator Award to Hani Suleiman, MD, PhD, an instructor at the Washington University School of Medicine, to use this new microscopy approach to look at kidney podocyte cells.

Recently, we spoke with Dr. Suleiman to hear about his work using this new microscopy approach, and how it might be used in the future to diagnose and potentially change how we approach creating new treatments for FSGS, Minimal Change Disease, and other diseases that cause Nephrotic Syndrome.

Dr. Hani Suleiman in his lab.

NKI: You received the Young Investigator Award from NephCure in 2014. Could you give us an overview on what you’ve been studying since receiving this grant?

Dr. Hani Suleiman: Glomerular diseases like Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are diseases of the podocyte, an important component of the kidney’s glomerular filtration barrier. Studying podocytes in living tissue has been limited due to the types of microscopy techniques that we use. The problem with seeing and understanding the podocyte and its changes is in its scale: important structures in the podocyte range from 200-300 nanometers. This resolution is below the limit of conventional microscopy techniques. Thus, we have been hindered from studying in detail the molecular changes that accompany podocyte injury and proteinuria.

Until the invention of super-resolution microscopy, the only way to view changes in podocytes after injury was to use electron microscopy techniques [electron microscopy was invented in the 1930s]. However, electron microscopy only allows us to see the structural changes in the podocyte. There is another technique that is capable, to some extent, to view the molecular patterns in podocyte structures after injury, but this technique has its own limitations. This is where super-resolution microscopy, a revolutionary new technique, comes in. We were the first people to adapt this technique to the kidney field.

In kidney diseases such as FSGS and MCD, podocytes go though a massive change in their shape as they lose their foot processes and form what is called foot process effacement. This is when the finger-like protrusions that you see in a normal podocyte change and basically disappear. This usually accompanies a leaky glomerular filtration barrier, as the patient starts spilling protein in the urine (proteinuria). Proteinuria, by itself, is an important indicator that the kidney is not functioning correctly as a filter.

Normal kidney podocyte.

Foot process effacement is a phenomenon that we see in almost all podocyte injuries, no matter how the injury starts: whether it’s immune-related, MCD or FSGS. All these diseases have foot process effacement and are accompanied with a loss of the glomerular filter.

In the paper that we just got accepted in the Journal of Clinical Investigation-Insight, we studied the molecular changes that accompany foot process effacement using super-resolution microscopy to try to understand the enigmatic phenomenon of foot process effacement and how foot process effacement is related to the cause of the injury. I think that, by mapping the earlier molecular changes in the injured podocytes, we can potentially intervene and stop this massive change and maintain the foot processes and the barrier.

This effort may be a good first step towards actually interfering with the pathways that we think interplay with this phenomenon [i.e., a first step towards treating proteinuria at a molecular level]. And for that, super-resolution will be an instrumental technique, since we are able to see the molecular changes of the cell on a nanoscale.

NKI: So podocyte foot process effacement is basically the fingerlike protrusions of the podocytes pulling up and away and leaving the podocyte with just the cell membrane. And without the fingerlike protrusions there, there’s nothing preventing the protein from leaking through the kidney?

Dr. Suleiman: As a response to injury, we think that foot process effacement is a survival mechanism for the podocytes. Podocyte number, like neurons, is a fixed number, and they must survive throughout life as they don’t reproduce. We can speculate that podocytes sense the dangers around them and respond by changing their shape in order to hold on to the basement membrane tightly as a precaution, in order to not fall into the urine. As I mentioned earlier, foot process effacement is usually accompanied with proteinuria, indicating that the retracted podocytes are unable to cover the whole basement membrane and prevent the protein leakage.

My work is to try to understand the earlier changes that cause the podocytes to go through this tremendous morphological change (i.e., foot process effacement), and how foot process effacement is related to the cause of the injury. I think that, by mapping the earlier molecular changes in the injured podocytes, we can potentially interfere and stop this massive change and maintain the foot processes and the barrier.

Dr. Suleiman, top row, second from the left, at the 2016 St. Louis NephCure Walk.

NKI: Are you mostly looking at mouse models right now?

Dr. Suleiman: In our recently accepted paper, we studied podocyte injury in three different mouse models. We included a small group of human tissue samples of FSGS, MCD and diabetic nephropathy in the study. We found that, similar to our mouse injury models, injured human podocytes show molecular changes that involve the motor molecules, myosin IIA.

As these results are in their early stages, I recently received a NEPTUNE (Nephrotic Syndrome Study Network) grant to study the biological significance of myosin IIA changes in human tissue samples. This study might allow us to find better diagnostic or prognostic tests for diseases such as MCD, FSGS and diabetic nephropathy.

NKI: So what you’re saying is that you think one day we might be able to use the super-resolution microscopy technique to diagnose patients?

Dr. Suleiman: Yes, I can see that the super-resolution microscopy will be instrumental in the future to diagnose and predict the outcome of diseases like glomerular diseases. The whole problem with imaging the podocyte in the past was the scale. Super-resolution, and the recently developed near super-resolution microscopy techniques, has the right scale to view the molecular changes in the podocytes.

NKI: Did the NKI Young Investigator Award have a big impact on what you have been able to do? Where were you at in your research when you received it?

Dr. Suleiman: Oh sure! That was my first grant ever. So for the last two years I have been relying on this grant to do my research. Of course, my previous mentor, Dr. Andrey Shaw, was highly supportive; I was still in his lab when I received the NKI award. This award has helped me publicize my work, refine my hypothesis and maintain my focus on the podocyte biology. It helped a lot. Thank you so much.

Hani Suleiman, MD, PhD, is an Instructor in the Nephrology Division at the Washington University School of Medicine in St. Louis. Upon establishing the use of super-resolution microscopy, STORM in the kidney field, Dr. Suleiman has been focused on utilizing this technique to study various kidney diseases such as diabetic nephropathy, focal segmental glomerulosclerosis, and minimal change disease. In 2017, he received the Nephrotic Syndrome Study Network (NEPTUNE) Career Development Fellowship.

Dr. Suleiman has developed new ways to image the podocyte’s actin cytoskeleton in both animal models and human. These methods will allow us to ask new questions regarding how podocytes regulate their unique shape and maintain their function throughout life.

Research Opportunities at the NIDDK

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is the branch of the National Institutes of Health (NIH) that focuses on funding research related to FSGS, Nephrotic Syndrome, and other kidney diseases. In 2016, they funded $574 million worth of research projects, and they continue to be a leader in clinical trials.

Currently, there are two clinical trials being held at the NIDDK that are relevant to the Nephrotic Syndrome community:

Goal of the study: To determine the safety and effectiveness of combining rituximab and cyclosporine to treat membranous nephropathy

Eligibility: Individuals 18 years of age and older who have been diagnosed with membranous nephropathy based on a kidney biopsy done within the preceding 24 months, and who have had excess levels of protein in the urine for at least 6 months based on urine and blood tests.

Summer Research Roundup

Summer is a great time to catch up on reading! If you’re sick of beach novels or historical biographies, consider catching up on science reading with our pick of recently published articles.

We combed through the literature and found some interesting and relevant publications that may be relevant to Nephrotic Syndrome patients and families. The articles are listed in no particular order, and we do not endorse or prefer any of the research studies.

Abstract:Steroid-resistant nephrotic syndrome (SRNS) is an important cause of chronic kidney disease (CKD) in children that often progresses to end-stage renal disease (ESRD). Calcineurin inhibitors (CNIs) have been shown to be effective in inducing short-term remission in some patients with SRNS. However, there are little data examining their long-term impact on ESRD progression rates. We performed a retrospective chart review of all patients treated for SRNS with CNIs at our institution from 1995 to 2013. Data collected including demographics, initial response to medical therapy, number of relapses, progression to ESRD, and treatment complications. A total of 16 patients met inclusion criteria with a mean follow-up of 6.6 years (range 0.6–17.6 years). Histopathological diagnoses were focal segmental glomerulosclerosis (8), mesangial proliferative glomerulonephritis (4), IgM nephropathy (3), and minimal change disease (1). Three patients (18.8%) were unresponsive to CNIs while the remaining 13 (81.2%) achieved remission with CNI therapy. Six patients (37.5%) progressed to ESRD during the study period, three of whom did so after initially responding to CNI therapy. Renal survival rates were 87, 71, and 57% at 2, 5, and 10 years, respectively. Non-Caucasian ethnicity was associated with progression to ESRD. Finally, a higher number of acute kidney injury (AKI) episodes were associated with a lower final estimated glomerular filtration rate. Despite the majority of SRNS patients initially responding to CNI therapy, a significant percentage still progressed to ESRD despite achieving short-term remission. Recurrent episodes of AKI may be associated with progression of CKD in patients with SRNS.

Abstract:
Focal segmental glomerulosclerosis (FSGS) is a frequent glomerular kidney disease that is revealed by proteinuria or even nephrotic syndrome. A diagnosis can be established from a kidney biopsy that shows focal and segmental glomerulosclerosis. This histopathological lesion may be caused by a primary podocyte injury (idiopathic FSGS) but is also associated with other pathologies (secondary FSGS). The first-line treatment for idiopathic FSGS with nephrotic syndrome is a prolonged course of corticosteroids. However, steroid resistance or steroid dependence is frequent, and despite intensified immunosuppressive treatment, FSGS can lead to end-stage renal failure. In addition, in some cases, FSGS can recur on a graft after kidney transplantation: an unidentified circulating factor may be implicated. Understanding of its physiopathology is unclear, and it remains an important challenge for the scientific community to identify a specific diagnostic biomarker and to develop specific therapeutics. This study reviews the treatment of primary FSGS and the recurrence of FSGS after kidney transplantation in adults.

Abstract:The etiology of nephrotic syndrome is complex and ranges from primary glomerulonephritis to secondary forms. Patients with nephrotic syndrome often need immunosuppressive treatment with its side effects and may progress to end stage renal disease. This review focuses on recent advances in the treatment of primary causes of nephrotic syndrome (idiopathic membranous nephropathy (iMN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS)) since the publication of the KDIGO guidelines in 2012. Current treatment recommendations are mostly based on randomized controlled trials (RCTs) in children, small RCTs, or case series in adults. Recently, only a few new RCTs have been published, such as the Gemritux trial evaluating rituximab treatment versus supportive antiproteinuric and antihypertensive therapy in iMN. Many RCTs are ongoing for iMN, MCD, and FSGS that will provide further information on the effectiveness of different treatment options for the causative disease. In addition to reviewing recent clinical studies, we provide insight into potential new targets for the treatment of nephrotic syndrome from recent basic science publications.

Abstract:Autoimmune thyroiditis (AIT) is generally associated with hypothyroidism. It affects ~2% of the female population and 0.2% of the male population. The evidence of thyroid function- and thyroid autoantibody-unrelated microproteinuria in almost half of patients with AIT and sometimes heavy proteinuria as in the nephrotic syndrome point to a link of AIT with renal disease. The most common renal diseases observed in AIT are membranous nephropathy, membranoproliferative glomerulonephritis, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, and amyloidosis. Different hypotheses have been put forward regarding the relationship between AIT and glomerulopathies, and several potential mechanisms for this association have been considered. Glomerular deposition of immunocomplexes of thyroglobulin and autoantibodies as well as the impaired immune tolerance for megalin (a thyrotropin-regulated glycoprotein expressed on thyroid cells) are the most probable mechanisms. Cross-reactivity between antigens in the setting of genetic predisposition has been considered as a potential mechanism that links the described association between ANCA vasculitis and AIT.

Abstract:IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic “hits”. An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O-galactosylated IgA1 and the inciting factors for the production of O-glycan-specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression.

Why I Do What I Do: Spotlight on Dr. Peter Mundel, Kidney Disease Researcher

Dr. Peter Mundel is a physician-scientist who has spent the past 30 years studying kidney cells called podocytes, which are specialized cells with a central role in glomerular diseases like FSGS. Dr. Mundel has been an esteemed member of NephCure’s Scientific Advisory Board since 2007, and in 2011, NephCure helped fund his work by providing him with a bridge grant.

A major focus of his work has been the development of new, targeted treatments for patients with FSGS and other glomerular diseases. Last year, he left his professorship at Harvard Medical School/Massachusetts General Hospital to lead the research of a new start-up company called Goldfinch Bio, a biotechnology company that is singularly focused on discovering and developing precision therapies for kidney disease. We spoke with Dr. Mundel about his work and what inspired him to leave academia to create new treatments for people living with FSGS and Nephrotic Syndrome.

NKI: How did you first become interested in studying the kidney? What is it about glomerular diseases specifically that interests you?

Dr. Peter Mundel

Dr. Mundel: I first became interested in studying the kidney when I was in medical school, back in Germany in the late ‘80’s. I had joined the laboratory of Dr. Wilhelm Kriz, who was one of the leading investigators in the field. At that time, there was nothing known about podocytes. They were considered passive bystanders. Everybody was thinking about mesangial cells and their role in the pathogenesis of kidney disease. So, I saw an opportunity and I entered the field and started to work on podocytes, and that’s what I focused on for 30 years since then: I got into the biology of these cells, learned about their function in health and disease, and then later of course I was trying to find podocyte-targeted therapies. But it all started 30 years ago in medical school in Germany.

I still remember how I would sit with Professor Kriz in his office and we would say “one day we should develop podocyte protective medicines.” That’s what we said, and 30 years later, we’re doing it!

NKI: Could you tell us about your discovery process of deciding to study a new drug? I am thinking specifically of abatacept because many people in our community are familiar with it, and I know you were instrumental in discovering its use in treating Nephrotic Syndrome.

Dr. Mundel: We can definitely talk about the abatacept story, because it has good parallels, and it also helps explain what brought me to Goldfinch Bio.

We identified B7-1/CD80 in podocytes, way back at my lab in Heidelberg, using differential Display PCR, a technique that allows you to monitor changes in gene expression between normal and diseased cells. We had our first paper on B7-1 in 2004 in The Journal of Clinical Investigation, where we showed that B7-1/CD80 has a role in podocytes in proteinuria, in addition to its role in the immune system. We studied the role of B7-1/CD80 in podocytes for another for 10 years, and then we began studying the use of abatacept [which targets CD80/B-71] in patients.

What’s interesting with abatacept is that we now know that there is a subgroup of patients that respond well to this drug. Going forward, the challenge will be in identifying with precision who are these patients for whom it will work. There is no silver bullet: not every patient with Nephrotic Syndrome and FSGS will respond to the same drug. Some people will respond to abatacept and some people will respond to some as-yet-unidentified new drug. We will need to take a precision medicine approach.

Knowing this, we will now need to define patients molecularly—not by saying they have FSGS or proteinuria, but by saying they have proteinuria driven by CD80/B7-1, or by protein ‘X’ or protein ‘Y’. That is exactly what our colleagues in oncology do: when you have a mutation in BRAF [which causes, for example, skin cancer or melanoma], you get a BRAF blocker for your melanoma.

At Goldfinch, we are basically bringing the oncology playbook to the kidney space. We need to figure out who will respond to which drug, and we will need to use people’s genetics to identify targets for new, specific drugs. I think abatacept was the first stop at personalized medicine. When our paper [on abatacept] came out, there was an accompanying editorial by Börje Harraldsson that said exactly that—“A New Era of Podocyte-Targeted Therapy.”

There is a trial going on with abatacept right now. I’m very pleased about that, because if you see in our original New England Journal of Medicine (NEJM) paper, patient number 5, this woman was on and off all kinds of drugs. But abatacept works so well for her that she is now in complete remission. And now, in her late 20’s, for the first time she has a good life; she enjoys her life. She doesn’t go from medicines with side effects to being hospitalized as she used to.

I think this is a great success, because this is an idea that started in my lab almost 20 years ago. Because of this work, there is someone who really feels good and has a good life. And so as I said, the challenge now is to find all those patients who will respond to each of our precision treatments.

NKI: Wow. That must make you feel incredible to know that years and years of your research led to this woman finally feeling like she could have a good life.

Dr. Mundel: It’s a humbling experience. It’s very humbling that I had the privilege to have an impact on someone’s life. Because you see, I’m an MD by training, but after medical school I have only done research. But indirectly I act like a physician—I don’t treat her myself, but because of my work, she now has a better life, and I’m very happy for her. For all of our patients at NephCure that we care about with FSGS and Nephrotic Syndrome, I think this is a beacon of hope. For some of them [abatacept] will work too, and for others we will now find new drugs. But it clearly shows that the overall idea of finding podocyte protective drugs is a good idea, and it can work.

NKI: So in the future, how would what you’re describing work? Would patients come in to their clinician and have gene mapping done, and when the results come in, their clinician would know exactly how to treat them?

Dr. Mundel: That is basically the end goal. At Goldfinch, we are building a patient registry where we will sequence thousands of patients with FSGS. This will allow us to stratify patients, so when we have a drug that we know will work for a certain pathway or mutation, we will be able to select patients who can benefit from this drug. We will be able to say, “You have a mutation in protein ‘X’, so we are giving you a drug correcting the effects of protein ‘X’ mutation.” That’s the targeted approach that we’re talking about when we refer to precision medicine.

At the same time, we need to identify more causes of FSGS. The work done by Dr. Martin Pollak and Dr. Friedhelm Hildebrandt has identified a lot of these genes, and there are even more to be found. What their work shows is that there is a genetic underpinning of FSGS. At Goldfinch, we will continue that work and work closely with many academic collaborators.

So to answer your question more directly, down the road what you described is exactly what we are going to bring to patients with kidney diseases. At some point, the patient comes in and they have proteinuria, and their doctor will do a genetic test. Right now, we can do it for about 70 or 80 genes [that are associated with FSGS and Nephrotic Syndrome], somewhere in that ballpark. Down the road, there may be hundreds, and patients will be tested for them. And we will have different medicines, so based on the patient’s mutation, we will be able to give them a specific treatment. We will no longer give patients nonspecific steroids or cyclosporine, but instead give them a targeted medicine because we will understand exactly what’s causing the disease. That’s what we want to do at Goldfinch—bring this personalized medicine to patients with FSGS.

NKI: Right, and that way they’re not wasting time cycling through drugs that aren’t working, and in the meantime, not just not having a very great life, but also heading towards end stage kidney disease. That will save a lot of time.

Dr. Mundel: Exactly. That’s the other goal—we want to prevent patients with FSGS to progress to end stage kidney disease and from going on to dialysis. At Goldfinch, our goal is to prevent people from going on to dialysis or needing a transplant—to stop the disease in a specific way by addressing the root cause.

NKI: This is fascinating. And before you mentioned Dr. Pollak and Dr. Hildebrandt’s work, which has been funded in part by NephCure, I was going to refer to it and say, it’s really interesting from an outsider’s view how all this research is culminating: the genetic research, and drug discovery research, and podocyte research. It seems like it’s finally all coming together.

Dr. Mundel: Oh, absolutely. Let me give you a prime example. My own work has been focused on the podocyte actin cytoskeleton. Independently, over the last five or six years, geneticists identified several FSGS causing mutations affecting the podocyte cytoskeleton. We now understand the genetics of the podocyte cytoskeleton, and this dovetails with what we understand about the biology. We are living in a time when genetics and biology are coming together. When you have both, then you can have the precision and the tools to make a targeted therapy.

NKI: Wow, what an exciting time to be a glomerular disease researcher. That excitement and that feeling of being just around the corner, that must have been part of what led you to leave academia. You had a very distinguished position at Harvard, and you left it to join Goldfinch Bio. That speaks volumes of your confidence in it.

Dr. Mundel: It does, and I believe that what we’re doing is the right thing. I’ll tell you, when I first came to Harvard in 2010, I thought I would continue doing academic research until I die in my office. And then this amazing opportunity came. As we discussed, it’s the dovetailing of the biology and the genetics, but also the work done by Dr. Melissa Little and by Dr. Joseph Bonventre, who’s one of our founders. They showed that it is possible to make kidney organoids, which are “kidneys in a dish”. So now we have the ability to study human kidney disease, if you will, in a dish. There’s also been an explosion of technical data, where analyzing the genetic data is becoming cheaper and cheaper. And cloud computing has arrived, which we didn’t have five years ago. Now we have all the computational tools, the biological tools, the genetic tools to bring such a push to this field. It’s absolutely exciting.

In 2008 we had a manuscript where we showed how cyclosporine, which is clinically used to treat NS, works on podocytes. Then we had the NEJM paper where we repurposed the drug abatacept from Rheumatoid Arthritis to patients with FSGS. Joining Goldfinch was the next logical step. I want to make new drugs targeting the causes of the diseases, and I think Goldfinch is the perfect place to do it.

And as you said my confidence is reflected in the fact that I have left Harvard. I’m not on a leave of absence, I have not kept my professorship; I have shut down my laboratory and returned all my grants and funding. I want to focus on Goldfinch now, because by focusing on it we can do our best. I wholeheartedly believe in what we are doing here, and I wholeheartedly believe that we will be successful in helping our patients. They really need new treatments. There are no drugs approved in the US to treat FSGS, and the last approved therapy to treat proteinuric kidney disease occurred over 20 years ago. It is pretty much the same since I graduated from medical school in 1991 . It’s time to bring a renaissance and provide new therapies for our patients. For me there is no better mission than doing that.

The goldfinch was a prominent symbol during the Renaissance, and signified hope and a new beginning. We chose to name our company Goldfinch Bio because we feel that the vision of our company is to lead a renaissance in developing new therapies for patients with kidney disease. I think it’s a sign of hope and optimism that there’s a new chapter, a new age that we are ushering in and that we want to lead. Because the patients deserve that we find good therapies for them. I’m proud to be part of the team here at Goldfinch that will do exactly that: find new therapies for patients with kidney disease. For me there’s nothing better that I can think of doing with my time.

We were thrilled to speak with Dr. Mundel and learn more about his latest venture. Researchers like Dr. Mundel and many others provide us with real hope and conviction that we will one day find a cure for the diseases that cause FSGS and Nephrotic Syndrome. Since 1999, NephCure has helped provide funding for more than 50 research projects to learn more about causes and potential cures for the diseases that cause Nephrotic Syndrome. Today, these researchers are closer than ever to moving new treatments from the laboratory to the pharmacy shelf. Thank you for your commitment to this work, Dr. Mundel, and all who have dedicated their lives to eliminating these rare and chronic diseases!

Dr. Peter Mundel is a past awardee of the esteemed American Society of Nephrology Young Investigator Award and a distinguished investigator who lead the Mundel Laboratory at Massachusetts General Hospital and Harvard Medical School from 2010 to 2016. In April 2014, Dr. Mundel received, jointly with Dr. Anna Greka, Renal Division, Brigham and Women’s Hospital, a 2014 Top 10 Clinical Research Outstanding Achievement Award from the Clinical Research Forum. In 2013, he and distinguished colleagues published the first targeted treatment for proteinuric kidney disease in the New England Journal of Medicine. (Abatacept in B-71; N Engl J Med 2013; 369:2416-2423). The associated editorial in the NEJM describes their discovery as a “New Era of Podocyte-Targeted Therapy for Proteinuric Kidney Disease.”

Dr. Mundel attended medical school at the University of Heidelberg, Germany. He completed a Postdoctoral Research Fellowship in the program “Experimental Kidney and Circulation Research” at the University of Heidelberg, which was funded by the German Research Foundation. He is also the author or co-author of over 86 original research articles. Dr. Mundel’s research focus has been on the makeup and function of podocytes, key cells found in each of the one million separate filtration units packed into a single human kidney.

NephCure Funded Research: Dr. Evren Azeloglu

Dr. Evren U. Azeloglu

In 2015, Dr. Evren Azeloglu, a biomedical engineer and an Assistant Professor at the Icahn School of Medicine at Mount Sinai, was awarded the NephCure Kidney International-ASN Foundation for Kidney Research Grant. He planned to use this grant to explore how kidney cells retain their structural integrity against mechanical injury.

Much of the work done in Dr. Azeloglu’s lab involves the podocyte, the specialized kidney cell that is affected by glomerular diseases like FSGS. Podocytes play an important role in glomerular function. Together with other cells, they help form a filtration barrier in the kidney, and they cooperate with other cells to support the structure and function of the glomerulus.

Below, we discuss Dr. Azeloglu’s latest research and what it means for people living with glomerular kidney diseases in our search for better treatments and a cure.

NKI: You’ve recently released two articles (here and here), both from research funded in part by NephCure. Can you tell us about your latest research?

Dr. Azeloglu: Well, podocytes have a very beautiful structure, and we used cutting-edge imaging technology to capture the three-dimensional geometry of these cells. This paper is essentially about how the podocyte shape is not just pretty and sophisticated, but also very necessary for their function. And their shape has certain consequences for disease: some of the glomerular diseases may be directly borne out of the fact that these cells are shaped this way. If you look at the below gif, you will see how these cells look in the body. This is the first time anyone has ever visualized them with this kind of precision.

NKI: Can you elaborate on what you mean when you say that their form suits the function?

Dr. Azeloglu: Well let’s say that you want to build a drawbridge, and you want to be able to have tall ships travel below or through it. So you can either spend a lot of money and build a very tall bridge that is stationary, or you can build one that opens and closes. Basically, you are proposing a “functional upgrade” to a regular bridge. Unfortunately, that comes at a cost. The bridge needs to be able to separate in the middle.

Following that analogy, podocytes have this special shape that allows them to do something that no other cell can do. What we are showing in our paper is that this special shape also comes with a price: incredible fragility. This works in the same way that a drawbridge has less stability than a regular arched bridge and would not be able to sustain the same level of, for example, an earthquake. You sacrifice that stability because you want to be able to open it up. In the same way, podocytes have incredible surface area; they have this amazing structure that allows them to filter blood plasma into urine, but what we’re showing is that only at this shape, the cells start showing this incredibly fragile behavior, and even a little change of their chemistry leads to disease.

This ties in very well with the current knowledge that the podocytes are sort of the first guys to fail, if you will. This is one of the reasons why, for example, diabetic patients, whose cells are under constant stress because of insulin spikes, high levels of glucose, and all sorts of other oxidizing agents, are much more likely to develop nephropathy. So, what we are trying to show here is that these cells are incredibly fragile compared to most other cells in our body.

NKI: What does it mean to be a biomedical engineer studying podocytes, and from a larger perspective, kidney disease?

Dr. Azeloglu: I approach kidney research from an engineer’s perspective: the same way we study machines, buildings, and structures that have to withstand physical stress, which is exactly what podocytes have to do day in and day out. What we’re looking for, and what most of the projects in my lab focus around is: can we understand what makes these cells more susceptible to physical damage, and perhaps reinforce their structure? When all’s said and done, podocytes form a filter, which has a biological function, but to achieve that function, the podocyte uses a very simple physical mechanism: forming a sieve. So we ask, can we come up with therapeutic strategies that can make the podocytes stronger and more resilient? Or can we identify how specific chemical and biomechanical assaults weaken them?

NKI: So is your lab directly looking at ways to fortify the cell? Or is that something you’re laying the groundwork for, for someone else to build from.

Dr. Azeloglu: To be able to fortify something, you want to be able to understand it first. There’s been a lot of science over the last two decades showing that a lot of what these cells do is basically prepare for constant physical abuse, for lack of a better word. It’s just not very pleasant to be a podocyte. It’s biologically expensive to try to maintain physical integrity. So “Part One” of my lab’s research program is: to try to understand what makes these cells unique and special, what is the repertoire of these cells for withstanding physical stress. And “Part Two” is: if we can understand it, can we eventually fortify it? Can we prevent this structure from failing under disease conditions? These cells are very fragile, and they need all the help they can get. We’re expecting them to stick around for 80 years — that’s a long time to be under constant physical abuse.

Dr. Azeloglu (pictured second from left) and his Systems Bioengineering Laboratory team at the Icahn School of Medicine at Mount Sinai.

NKI: The podocyte is such a specific cell—how did you become interested in studying it exclusively?

Dr. Azeloglu: Partly because of the video that you’re looking at—they’re really unique. They’re also almost a poster child of physical cellular stamina. They’re a great example of a microscopic structure that has evolved to do a very specialized physical task and do it for an extended period of time. It’s sort of a dream come true for an engineer.

NKI: What stage were you at in your research when you received this award? Did it have a big impact on what you were able to do?

Dr. Azeloglu: Oh, absolutely! I had just received my appointment as an Assistant Professor, and I had just started setting up my own lab. Without this, I basically wouldn’t have been able to do that.

I come from a cardiac background—as a biomedical engineer, I trained in a cardiac biomechanics lab. And the heart, being a mechanical pump, is another example of a living tissue that’s doing a physically demanding job. I studied that for ten years and as I was transitioning into nephrology, the NephCure-ASN Award was critical. It helped me establish myself as an expert in this field as well. It’s sort of a rite of passage—a lot of the fellows who’ve received this award have moved on to successful careers, so it’s almost expected for you to have one to establish yourself in the field.

I also think my goals and the goals of the NephCure-ASN Award align very well. I want to understand these cells from an engineer’s perspective, which I think is very relevant to their function, and if we can understand it, I think we’ll be able to cure diseases like FSGS. We’ll be able to not only help patients in terms of their symptoms, but also actually cure the disease. I’m in a pharmacology department, so I know that our standard methods can only help us so far; hopefully, this new, fresh perspective will be able to take us to the next level: instead of just dealing with the symptoms, we’ll be able to cure kidney disease. Hopefully.

We were delighted to speak with Dr. Azeloglu on the results of his current research. If you want to stay updated on his work, you can follow him on Twitter (@azeloglu) or visit his lab’s website at http://labs.icahn.mssm.edu/azeloglulab. Thank you for your dedication to this work, Dr. Azeloglu and team!

Dr. Evren U. Azeloglu is an Assistant Professor in the Department of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. He was originally trained as a mechanical engineer, but later went on to receive his Ph.D. in biomedical engineering from Columbia University. In 2010, Dr. Azeloglu was awarded the Howard Hughes Medical Institute Fellowship from the Life Sciences Research Foundation. His background in biomechanics and systems biology is uniquely positioned to study complex diseases such as hypertension and diabetic nephropathy. He aspires to design transformative therapeutic tools using nanotechnology and tissue engineering.

The NACI Network is expanding worldwide to speed more effective treatments to individuals with Nephrotic Syndrome

Thanks to a significant funding contribution, we’re proud to announce that the NephCure Accelerating Cures Institute (NACI) Care Network is expanding. An investment from Pfizer’s Centers for Therapeutic Innovation (PFE) and Retrophin (RTRX) will help grow the network from 8 sites to 30 sites worldwide. For patients living with Nephrotic Syndrome, more NACI sites means greater access to specialized care and trial opportunities specific to their unique kidney condition. Equally important, a more robust Network gives families across the globe a hub for community building and support at their individual care sites.

NephCure Accelerating Cures Institute Global Trials Network

The NACI story began in 2014, when leaders from NephCure Kidney International sought advice from leading medical professionals about ways to get better treatment options to patients faster. That following year, NKI launched NACI in partnership with the University of Michigan. Today, NACI is co-led by veteran representatives from NKI in suburban Philadelphia and an expert team from the University of Michigan, Ann Arbor.

NephCure Accelerating Cures Institute United States Trials Network

To read more about NACI, you can view the full press release here, or visit the NACI website at www.nephcureaci.org. If you have any questions or want to learn more, please send us an email at info@nephcure.org, and we will direct your message to the appropriate party.

NephCure Funded Research: Dr. Martin Pollak’s Lab

Through generous donations from the NephCure Kidney International community, NephCure has been able to support Dr. Martin Pollak’s kidney disease research at Beth Israel Deaconess Medical Center (a Harvard Medical School teaching hospital) since 2007. Dr. Pollak’s lab works on identifying genetic causes of kidney diseases, like FSGS. They have made some very exciting progress over the past few years, leading to Dr. Pollak’s election into the prestigious National Academy of Sciences in 2014.

Dr. Pollak’s research has identified that two common variations in the apolipoprotein L1 (APOL1) gene impart up to a ten-fold increased susceptibility to FSGS among African Americans. African Americans and others of recent African ancestry suffer disproportionately from chronic kidney disease: although they make up 13% of the U.S. population, they represent 35% of all individuals on dialysis. Other researchers have calculated that 1 in 8 African Americans are at risk for developing kidney disease due to APOL1—stark numbers that may indicate that some forms are FSGS would not be classified as a “rare disease.”

But the research being done at Dr. Pollak’s lab may one day help prevent treat—and prevent—this disease from occurring. Dr. Pollak was recently featured in an article on SFGate.com as saying that “We want to put our own [kidney disease research] division out of business by preventing this disease to begin with.”

We are thrilled to offer a “progress report” on this work directly from Dr. Pollak’s lab. We spoke recently with Andrea Knob, a genetic counselor, clinical research coordinator, and key player in Dr. Pollak’s study, who gave us some background on the work the study is doing, what we can expect from this lab in the future, and how you can get involved in this research yourself.

Q: What is the goal of the research being done in Dr. Pollak’s lab?Andrea: The purpose of our study is to learn more about the causes of kidney conditions including FSGS, Nephrotic syndrome, unexplained proteinuria, and renal failure by studying genetics. We identify and study genetic factors that may contribute to the development of these conditions. We hope that this will further the knowledge required for scientists to develop better treatments in the future.

Q: What is your role at Dr. Pollak’s lab?Andrea: I am the clinical research coordinator for Dr. Pollak’s lab. With my background in genetic counseling, I help patients and families navigate the research process, assist them in documenting their personal and family health histories, and serve as a resource for any questions surrounding genetics and research. I am the liaison between our patients/families and our physicians/scientists.

Q: What do you enjoy about CKD research?Andrea: Every person and family has a story to share, and this information is so valuable and so important. It is amazing to witness this generosity, and to be a part of a team that is so dedicated to making progress in this field. Research answers the questions that otherwise would be left unknown, and that in turn provides hope.

Q: What is APOL1?Andrea: APOL1 is one of several genes that we study in the Pollak lab. Variations in this gene have been found to confer resistance to trypanosomiasis, a serious disease in some African regions, and as such these variations have risen in frequency in parts of Africa. We are investigating how these gene variants contribute to kidney disease in persons of African ancestry.

Q: Why did the lab decide to focus on APOL1?Andrea: APOL1 is one of several genes that we study as we try to learn more about the causes of FSGS, Nephrotic syndrome, and related conditions in patients and families. Our lab’s interest in the genetics of FSGS led us to explore the basis of the high rate of FSGS in persons of African ancestry. Certain specific variations in the APOL1 gene contribute to this disparity.

Q: What impact can diagnosing an APOL1 mutation have on treatments for patients?Andrea: We need to learn more about genes, including APOL1, that may contribute to the development of kidney disease. (We also think there are more to be discovered!) Diagnosing a gene mutation helps doctors determine who might be at increased risk of developing kidney disease. While it may not affect the treatment for patients at this time, the goal is to acquire the information we need about these gene variations in order to develop better treatments in the future.

Q: What is involved for patients in this study?

Andrea: Participation involves a questionnaire, a saliva sample, and a urine sample (if possible) that can be given from home. (If participants prefer to give a blood sample instead of a saliva sample we can help arrange this.)

Q: Who can participate in this study?Andrea:• Anyone with FSGS, Nephrotic syndrome, or unexplained proteinuria
• Anyone with a family member who has FSGS, Nephrotic syndrome, or unexplained proteinuria
• Anyone with African ethnicity with non diabetic kidney failure
• Any healthy individual without kidney disease

Q: How do I get more information about the study?
Contact Andrea Knob with any study related questions by phone at 617-667-0467 or by email at aknob@bidmc.harvard.edu. You can also read more about the research study by clicking here.

Organizational Mission

NephCure Kidney International ® is the only organization committed exclusively to support research seeking the cause of the potentially debilitating kidney disease Focal Segmental Glomerulosclerosis (FSGS) and Nephrotic Syndrome, improve treatment and find a cure.